H-12 : immunosuppressive regimens
H- 15 : drug-related complications
Risk of Metabolic Complications in Kidney Transplantation After
Conversion to mTOR Inhibitor: A Systematic Review and MetaAnalysis
N. Murakami1, L. V. Riella2,†,* and T. Funakoshi1,†
Article first published online: 21 AUG 2014
DOI: 10.1111/ajt.12852
American Journal of Transplantation Volume 14, Issue 10, pages 2317–2327, October
2014
ABSTRACT
Mammalian target of rapamycin (mTOR) inhibitors have been used in transplantation with the
hope of minimizing calcineurin inhibitor (CNI)-induced nephrotoxicity. However, mTOR
inhibitors are also associated with a range of side effects, including metabolic complications.
We aimed to determine the risks of metabolic complications after the conversion from CNI to
mTOR inhibitor postkidney transplant. A systematic search in PubMed up to September 2013
identified nine relevant trials (a total of 2323 patients). The primary end points were the
relative risks (RRs) of new-onset diabetes after transplant (NODAT) and
hypercholesterolemia. The overall RRs of NODAT and hypercholesterolemia associated with
mTOR inhibitors were 1.32 (95% confidence interval [CI] 0.92–1.87) and 2.15 (95% CI 1.35–
3.41), respectively, compared with CNI-based regimen. Subgroup analyses revealed no
differences in the incidence of NODAT or hypercholesterolemia between sirolimus- versus
everolimus-based regimen, or between early versus late conversion. Analyses of secondary
outcomes revealed a higher risk of acute rejection, proteinuria and anemia, but no difference
in the risk of opportunistic infections after mTOR inhibitor conversion. In conclusion, the
conversion from CNI to mTOR inhibitor in low-to-moderate risk kidney transplant recipients
was associated with nonsignificant trend toward increased risk of NODAT and significant
increase in hypercholesterolemia, acute rejection, proteinuria and anemia.
Keywords:

Calcineurin inhibitor (CNI);

clinical research/practice;

complication: medical/metabolic;

immunosuppressant;

immunosuppression/immune modulation;

immunosuppressive regimens;

kidney transplantation/nephrology;

mechanistic target of rapamycin (mTOR);

minimization/withdrawal
COMMENTS
Calcineurin inhibitor (CNI)-based regimens are most commonly used as maintenance
regimens after kidney transplantation because of their potent immunosuppressive activity.
However, long-term use of these agents has been associated with significant nephrotoxicity,
which may limit long-term graft and patient's survival.
Recently, conversion from CNI-based regimen to mammalian target of rapamycin (mTOR)
inhibitor-based regimen in early (1–6 months) or late (6 months or later) posttransplant has
been tested in multiple trials, showing overall improvement in graft function, though a high
discontinuation rate was observed in the mTOR inhibitor arm and some trials reported a
higher acute rejection rate.
Metabolic complications such as new-onset diabetes after transplant (NODAT) and
hypercholesterolemia have been reported to be caused by both CNI and mTOR inhibitor in
postkidney transplant recipients
A total of nine open-label RCTs were selected for the meta-analysis, including seven trials
reporting NODAT and nine trials reporting hypercholesterolemia.
A total of 2323 patients (SRL: 916, EVL: 384, controls: 1023) were available. All patients
underwent kidney transplant, switched from CNI to mTOR inhibitor in early (five trials, <6
months posttransplant) or late phase (four trials, >6 months posttransplant).
Results showed that the conversion from CNI to mTOR inhibitors did not decrease the risk of
NODAT (RR 1.32; 95% CI 0.92–1.87; p = 0.13) and was actually associated with a
nonstatistically significant increase in NODAT.
The incidence of hypercholesterolemia due to mTOR inhibitors was 30.5% (95% CI 16.2–
49.9) using the random-effects model (heterogeneity test: Q = 218.78; p < 0.001; I2 = 96.34).
For the control arm, the incidence was 13.0% (95% CI 4.8–31.0) using the random-effects
model (heterogeneity test: Q = 214.14; p < 0.001; I2 = 96.30). The risk of
hypercholesterolemia was higher with the use of mTOR inhibitors compared with the controls
(RR 2.15; 95% CI 1.35–3.41; p = 0.001.
In conclusion, this meta-analysis has demonstrated that conversion from CNI to mTOR
inhibitor in early or late posttransplant is associated with nonsignificant trend toward an
increased risk of NODAT and a significantly higher risk of hypercholesterolemia.
Pr. Jacques CHANARD
Professor of Nephrology